Following entry into the host cell, retroviruses can be blocked in the cells of certain species by dominant acting host factors. For example, human immunodeficiency virus (HIV-1), the etiologic agent of acquired immunodeficiency syndrome (AIDS), encounters a post-entry block in the cells of most Old World monkeys. By contrast, infection by the related simian immunodeficiency virus (SIV) is restricted in New World monkeys. Certain strains of murine leukemia viruses (MLVs) enter human cells but are blocked soon thereafter. All of these post-entry restrictions share common features: 1) the block occurs prior to or at the early stage of reverse transcription;2) the viral determinant of the susceptibility to restriction is the capsid protein;and 3) the host cell restricting factor can be competed by virus-like particles containing the restricted capsid. The factor restricting HIV-1 in rhesus monkeys has been identified as TRIM5alpha. The human orthologue can also inhibit HIV-1 infection, but not as efficiently as the rhesus monkey TRIM5alpha. In this application, we propose: 1) To identify the determinants of antiviral potency in primate TRIM5alpha proteins;2) To understand the impact of interspecies variation in TRIM5alpha on the ability of the protein to restrict particular retroviruses;3) To elucidate the mechanism of TRIM5alpha's potent antiviral effect.